WashU Study Sheds Light on Genome-Protection Pathway

Researchers at Washington University School of Medicine in St. Louis have identified a previously unknown signaling pathway cells use to protect their DNA while it is being copied. The findings suggest that targeting this pathway potentially could boost the potency of cancer therapeutics.

“A cell that can’t protect its genome is going to die,” said Zhongsheng. You, senior author of the study  published today in Molecular Cell. “This entire pathway we found exists to protect the genome so the cell can survive in the face of replication stress. By combining inhibitors of this pathway with chemotherapy drugs that target the DNA replication process, we potentially could make such drugs more effective.”

The pathway that You’s team discovered is described like this: When the DNA-duplicating machinery stalls, a protein called Exo1 that normally follows behind the machinery gets a little out of hand. Exo1’s job is to perform quality control by cutting out incorrectly copied pieces of DNA, but when the machinery stops moving forward, Exo1 starts snipping away haphazardly, cleaving off bits of DNA that then make their way out of the nucleus and into the main part of the cell. DNA is not found outside the nucleus under normal conditions, so its presence in the main part of the cell sets off an alarm. Upon encountering a fragment of DNA, a sensor molecule triggers a cascade of molecular events, including the release of the calcium ion from a cellular organelle known as the endoplasmic reticulum, which in turn shuts down Exo1, preventing it from dicing up the genome any further until the problem with the machinery can be fixed.

“Now that we have the pathway, we want to know whether it can be targeted for cancer treatment,” You said. “Lung, ovarian and breast cancer are intrinsically under replication stress. Other cancers are put under replication stress by chemotherapy drugs. This pathway protects cells from replication stress, so if we could block the pathway, it might improve patients’ response to cancer therapies.”

Several of the proteins in this pathway also play a role in other critical biological processes, including immunity, metabolism and autophagy, the process by which cells break down their own unwanted materials. “One of the most exciting things about this pathway is how it intersects with so many other pathways,” You said. “I’ve been focusing on cancer, but much of this could also apply to autoimmune diseases. Two of the proteins we identified have been linked to chronic activation of the immune response and autoimmune disease. We want to understand the relationship between this replication-stress response pathway and the innate immune response pathway. The work we do is very basic, and it is so exciting to connect the dots between these fundamental processes and see how they relate to human health and disease.”